CHOLESTEROL HOMEOSTASIS IN THE INBRED MOUSE

肠道是一个独特的器官，为人体提供膳食和重新吸收的胆道胆固醇。过量的胆固醇会导致胆固醇结石。胆石症在食用西方高胆固醇饮食的文化中很普遍，并且可以通过高胆固醇和胆酸饮食在小鼠模型中诱导。因此，了解胆固醇的吸收对预防和治疗胆固醇性胆结石具有重要意义。众所周知，遗传因素显然在近亲繁殖小鼠胆固醇胆结石的发展中起着关键作用。研究发现，C57L和AKR菌株之间的胆结石易感性差异是由至少两个Lith（胆结石）基因决定的，而p -糖蛋白（Spgp）的姊妹基因，小管胆盐转运蛋白是Lith1的候选基因。最近的一项观察发现，在11种近亲繁殖的小鼠中，在饲喂致石饮食8周后，胆固醇吸收百分比与胆固醇胆结石患病率之间存在显著的正相关，这强烈表明，肠道对胆固醇的吸收程度可能是胆固醇胆结石形成的遗传决定步骤。此外，据观察，对胆固醇胆结石的易感性存在性别差异，男性和女性的易感性是2:1。申请人提出了五个具体目标，以探索胆固醇稳态的遗传和生理机制，胆固醇吸收的分子机制，以及产石胆汁和胆固醇胆石症形成的病理生理机制。目的1：研究12种近交系小鼠胆固醇吸收效率的遗传变异及其在胆固醇胆结石形成中的作用。目的2：确定高胆固醇吸收和低胆固醇吸收小鼠胆固醇吸收和乳糜微粒形成的分子机制差异。目的3：研究餐后乳糜微粒代谢及其在胆汁成石中的作用。目的4：利用遗传胆结石易感小鼠和SR-B1基因敲除小鼠，阐明SR-B1 （HDL）受体在胆道胆固醇分泌和胆固醇胆结石形成中的作用。目的5：表征胆结石表型性别差异的激素基础。这些研究将为我们对胆固醇稳态的基本认识以及胆固醇胆石形成的发病机制提供重要贡献。

The intestine is an unique organ providing dietary and re-absorbed biliary cholesterol to the body. Excess cholesterol can result in cholesterol gallstone disease. Cholelithiasis is prevalent in cultures consuming a Western diet with high cholesterol, and can be induced in mouse models by a high cholesterol and cholic acid diet. Therefore, understanding cholesterol absorption is of great importance to both prevention and treatment of cholesterol gallstones. It has been known that genetic factors apparently play a critical role in the development of cholesterol gallstones in inbred mice. It has been found that differences in gallstone susceptibility between C57L and AKR strains are determined by at least two Lith (gallstone) genes, as well as that the sister of P-glycoprotein (Spgp), a canalicular bile salt transporter is a candidate gene for the Lith1. A recent observation that there is a remarkable positive correlation in eleven strains of inbred mice between percent cholesterol absorption and prevalence of cholesterol gallstones at 8 weeks of feeding the lithogenic diet strongly suggests that the extent of cholesterol absorption from the intestine may be a genetically determined step for cholesterol gallstone formation. Furthermore, it has been observed that there are gender differences in susceptibility to cholesterol gallstones, favoring males to females by 2:1. The applicant proposes five specific aims to explore genetic and physiological mechanisms of cholesterol homeostasis as well as molecular mechanisms of cholesterol absorption, and pathophysiological mechanisms of the formation of lithogenic bile and cholesterol cholelithiasis. Aim 1: To investigate genetic variations in cholesterol absorption efficiency and their role in cholesterol gallstone formation among 12 strains of inbred mice. Aim 2: To define differences in molecular mechanisms for cholesterol absorption and chylomicron formation between mice with high and low cholesterol absorption. Aim 3: To study postprandial chylomicron metabolism and its role in the lithogenesis of bile. Aim 4: Using genetically gallstone-susceptible and the SR-B1 att (knockout) mice, to elucidate the role of SR-B 1 (HDL) receptor in biliary cholesterol secretion and cholesterol gallstone formation. Aim 5: To characterize hormonal basis for gender differences in the gallstone phenotypes. These studies should provide important contributions to our basic understanding of cholesterol homeostasis as well as pathogenesis of cholesterol gallstone formation.